The liver is the site of many metabolic processes, including metabolism of xenobiotics such as pharmaceutical compounds. Drug metabolism is highly species specific and can vary significantly between individuals of the same species. To date no reliable experimental system capable of predicting the human-specific metabolic conversion of candidate small molecules exists. Our company (Yecuris Inc.) has developed an in vivo genetic selection system (the FRG mouse) that permits extensive humanization of murine liver by transplanted human hepatocytes. Preliminary data show that highly humanized mice (>80%) accurately reflect most aspects of human drug metabolism. Therefore highly humanized FRG mice are an attractive novel system for modeling human drug metabolism and pharmacokinetics at an early stage of drug development. However, the extent of liver humanization achieved in our mice currently remains highly variable, ranging from <5% to >90%. In order to make our platform more attractive to commercial customers and more commercially viable (reduced production cost per mouse), it will be necessary to reproducibly achieve high humanization levels in the majority of mice. In this phase 1 STTR application we propose 2 specific aims to advance our goal of reliable liver humanization: 1) We will test different background strains of mice for their ability to support high level liver repopulation. 2) The effects of different regimens to deplete/inhibit hepatic Kupffer cells on repopulation levels will be ascertained. PUBLIC HEALTH RELEVANCE: The animal model is an attractive novel system for modeling human drug metabolism and pharmacokinetics at an early stage of drug development. Commercialization of our technology will greatly reduce the cost of and accelerate new drug development, thus contributing to public health.